[PPT] - CDRH Scientific Perspective on Chemical Analysis and Toxicological PowerPoint Presentation

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CDRH Scientific Perspective on Chemical Analysis and Toxicological Risk Assessment for Medical Devices

Presenters: Berk Oktem, Alan Hood, Jennifer Goode Co-authors: Eric Sussman, Samanthi Wickramasekara

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www.fda.gov

Disclaimer

The findings and conclusions in this presentation have not been formally disseminated by the Food and Drug Administration, are the views of the authors, and should not be construed to represent any agency determination or policy. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by Department of Health and Human Services.

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Objective

Discuss common analytical chemistry and toxicological risk assessment issues related to the 2016 CDRH Biocompatibility Guidance, ISO 10993-18 and ISO 10993-17.

www.fda.gov

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Outline

1. Introduction: 21st Century Cures Act of 2016, least burdensome

approaches

2. Background: Why Chemical Analysis and Toxicological Risk

Assessment

3. Part I: Chemical Analysis Approaches
4. Part II: Toxicological Risk Assessment

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Introduction

21st Century Cures Act -Section 3058: Least Burdensome Device Review

CDRH Guidance :”The Least Burdensome Provisions: Concept and Principles”

February 2019. – We define “least burdensome” to be the minimum amount of information necessary to adequately address a relevant regulatory question or issue through the most efficient manner at the right time – The least burdensome provisions do not change the standards (i.e. level of information needed) for premarket approval or substantial equivalence – Least burdensome provisions form a ‘two way street’: “Industry should not submit information unrelated to the regulatory decision to FDA.”

www.fda.gov https://www.fda.gov/media/73188/download

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Background: Why Chemical Analysis and Toxicological Risk Assessment

2016 CDRH Biocompatibility Guidance

– “potential risks from a biocompatibility perspective should be identified” – “what information is already available regarding those risks and identify the knowledge gaps that remain” – “address the knowledge gaps either by biocompatibility testing or other evaluations that appropriately address the risks”

www.fda.gov https://www.fda.gov/media/85865/download

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2016 CDRH Biocompatibility Guidance – “Inherent in the review of medical devices is an understanding of the body’s entire exposure to the medical device, including all chemical entities contained within the device.” – “chemical analyses can be used to assess the toxicological risk of the chemicals that elute from devices. For example, chemical analysis using exhaustive extraction techniques (per ISO 10993-12) can also be helpful to evaluate long-term toxicity endpoints such as potential carcinogens…In addition, the outcomes of chemical analyses are often sensitive to the parameters of the test. Extraction solvents should be selected to optimize compatibility with the device materials ”

www.fda.gov

Background: Why Chemical Analysis and Toxicological Risk Assessment

https://www.fda.gov/media/85865/download

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Background: Applicability of Other Industry Approaches

Devices are not drugs
Devices are not pharmaceutical packaging
Devices are not food containers
Analytical approaches that generate data adequate for

toxicological risk assessment can be useful for medical devices

www.fda.gov

Material characterization of medical devices require unique approaches

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Background: Brief Comparison of Different Industries

www.fda.gov

Drug Products Medical Devices Contact Until expiration date 1 minute to lifetime Dose Single, multiple or repeated Single, multiple or repeated, continuously Impurities identification Leachables delivered with the drug product (tablet, liquid/solution) Extractables released from the device components that contacts the body indirectly

r directly.

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Part I: Chemical Analysis Approaches

– Expanded Information in ISO FDIS 10993-18:2019 – Chemical Analysis: Purpose-Contact and other Considerations – Considerations for Planning an Extraction Study and Analytical Tools – Identification of Non-targeted Extractables – Quantification and Reporting

www.fda.gov

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Part I: Chemical Analysis Approaches

Non-targeted screening:

Extraction: exhaustive or exaggerated extraction
Data generation: multiple analytical methods
Detect, identify and quantify: To provide data to support

toxicological risk assessment

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What Standards Are Used?

A standardized method for complete chemical analysis of medical

device materials does not currently exist.

CDRH partially recognizes ANSI AAMI BE83:2006/(R)2011 (there

are differences between ISO 10993-18: 2005 and BE83)

CDRH does not recognize PQRI recommendations (2006)
The "ISO FDIS 10993-18:2019 (recently balloted) includes additional

details on analytical instruments, quantification methods, etc."

www.fda.gov

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/search.cfm

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Expanded Information in ISO FDIS 10993-18:2019

Concepts that do not appear in ISO 10993-18:2005 – AET: Analytical Evaluation Threshold, a pre-determined concentration above which an extractable is expected to be identified and semi-quantified.(definitions) – The importance of identification (not new as concept but….) – Expansion of reporting requirements ….and more

www.fda.gov

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Analytical Evaluation Threshold: Reporting and Identification Limit

www.fda.gov Dose-Based Threshold (DBT) = Threshold of Toxicological Concern (ICH M7) A = number of medical devices extracted B = extract volume C = number of medical devices that contact the body D** = dilution factor (D>1), if concentrated (D<1). If not diluted (D=1) UF = uncertainty factor of analytical methods (UF >=1) **D is optional: extract processing should be accounted for.

ISO FDIS 10993-18: 2019, Annex E AET (μg/ml) = DBT (μg/day) x (A/(BxCxD)) ÷ UF

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Analytical Evaluation Threshold: Reporting and Identification Limit

www.fda.gov

Device Contact Duration DBT (µg/day) Limited and prolonged (<30 days) 120 Permanent/Long-term (>30 days) 1.5

AET > LOQ , LOD

Dose-Based Threshold (DBT) = Threshold of Toxicological Concern (ICH M7)

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Chemical Analysis Considerations

Common Questions:

Purpose: what biocompatibility endpoints are addressed?
Device Information
Test Article Information
Extraction
Analysis
Identification
Quantification

Note: Chemical equivalency involves different considerations and will not be discussed today.

www.fda.gov

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Purpose, Device and Test Article Information Considerations

Purpose: to support biocompatibility evaluation of some biological

endpoints (e.g., Acute Systemic Toxicity, Subacute/Subchronic Toxicity, Chronic Toxicity, Genotoxicity, Carcinogenicity)

Device information: material list (direct and indirect contact)
Test article information: final finished device, manufacturing

considerations

Information gathering: determine the scope of any analytical testing
Extraction design: rationale for solvent selection, time/temperature of

extraction, etc.

www.fda.gov

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www.fda.gov

Analysis Considerations

Duration of Contact

Limited (<24 h) Prolonged (1-30 days) Long-Term/ Permanent (>30 days)

Duration/ Number

f Cycles

Exaggerated extractions

r worst case clinically

relevant conditions Exhaustive extractions

r worst case clinically

relevant conditions Exhaustive extractions

Number of solvents

Polar and non-polar solvents (or polar and mid-polar if justified) Polar and non-polar solvents (or polar and mid-polar if justified) Polar, mid-polar and non-polar

NVR Analysis Performed?

NVR analysis may be considered NVR analysis to support if exhaustion is achieved NVR analysis to support if exhaustion is achieved

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System Suitability/Qualification

Establishing instrument sensitivity

Following practices for robust method

– 5 Point Calibration Curve – Use of internal standards – Use of more reference standards with varying response factors

Selecting reference standards: Use of reference standards that

match the expected/observed extractables can improve identification and quantification

– Example:

Polyvinyl chloride (PVC): DEHP
Polyurethane: 4,4’-MDI

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Considerations for Planning an Extraction Study and Analytical Tools

Non-targeted vs. targeted methods
Non-targeted (screening): detect, identify and semi-quantify

extractables above AET

Targeted: specific purpose (e.g. formaldehyde)

– Could include specialized methods (e.g. 2,4 DNPH derivatization for carbonyl compounds)

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Considerations for Planning an Extraction Study and Analytical Tools (cont.)

Comparison of equipment, temperatures:

Closed vessel in temperature controlled incubator / shaker

– Confirmation of agitation – Set temperature: e.g. 50 °C

Soxhlet extraction

– Losses of semi-volatiles, volatiles – Temperature variable depending on the boiling point of solvent

Accelerated Solvent Extraction (ASE)

– Not universal but may be applicable under certain conditions – Elevated temperature (up to 200°C) and pressure (1500psi)

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www.fda.gov

Time and temperature per ISO 10993-12 can be used as a starting point.

Considerations for Planning an Extraction Study and Analytical Tools (cont.)

Solvent Polarity Index Boiling point (⁰C) Polar Water 10.2 100 Saline (0.9 % NaCl) 10.2 100 Buffer: PBS, Tris etc. 10.2 100 Semi Polar Dimethyl sulfoxide 7.2 189 Acetonitrile 5.8 82 Ethanol 4.3 78 Tetrahydrofuran 4.0 65 Isopropanol 3.9 82 Dichloromethane 3.1 41 Non-Polar Toluene 2.4 111 Cyclohexane 0.2 81 Hexane 0.1 69 ISO FDIS 10993- 18:2019, Annex D

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Multiple methods to cover all types of chemicals:

HS-GC-MS : volatile organic compounds (VOCs)
GC-MS : semi-volatile organic compounds (SVOCs)
LC-UV-MS: non-volatile organic compounds (NVOCs)
LC-ELSD or CAD: non-volatile organic compounds (NVOCs)
ICP-MS : Elemental analysis, metals
FTIR, GPC, NMR, IC

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Analytical instruments: selected to be fit for the intended purpose.

Considerations for Planning an Extraction Study and Analytical Tools (cont.)

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Considerations for Identification of Non-Targeted Extractables

Purpose
Identification Levels: confident or better?
Identification Data: spectral library, supporting chemistry data, and

expert judgement?

www.fda.gov

Name of Compound CAS # Extraction Vehicle Analytical Instrument Major Ions

bserved (m/z)

RT (min) Identification level Identification Data Quantity (µg/device) Quantification Method and reference standard Diethyl phthalate 84-66-2 Hexane GC/MS 279,167,149 6.2 Confirmed Confirming Spectral library and RT match 10 Full-authentic reference std Irgafos 168 31570-04-4 Ethanol LC/MS 647.4608 7.25 Confident Library match plus Supporting data 2 Semi-quantitative; Tinuvin P

Supporting data can include, but is not limited to, generation of a single molecular formula, matching retention time (RT), functional group data (e.g., UV), absence of possible alternative isomers, etc.

Example of a Tabulated Identification Assessment (TIA)

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Considerations for Quantification

Quantitative/semi-quantitative analysis
Response factors
Spike and recovery
Duty cycle and ionization types
AET for non-targeted extractables

www.fda.gov

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Considerations for Reporting

www.fda.gov

Information for toxicological risk assessment (TRA)
Quantity in µg/device
Comparison of Non-Volatile Residue (NVR) and total mass observed

by all chemical methods

2016 CDRH Guidance has more (Section VII; Attachment E)….

https://www.fda.gov/media/85865/download

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What is a toxicological risk assessment?

Part II. Toxicological Risk Assessment

www.fda.gov

Why conduct a toxicological risk assessment?
When to consider toxicological risk assessment?
Current Status of CDRH Recognition of ISO 10993-17:2002(R)2012
Threshold of toxicological concern (TTC)
Margin of Safety (MOS)
How important is identification in toxicological risk assessment?
Status of ISO TC 194 WG11 documents

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The act of determining the potential of a chemical/compound to elicit an adverse health effect based on a specified level of exposure

What is a Toxicological Risk Assessment?

Hazard Exposure Dose +

Type Example Adverse effect Animal/human (age/sex), treatment doses, single, repeated, frequency/duration Supporting information Chemical/physical, QSAR, in vitro, ADME, mechanism, Secondary source Peer review publication, non- peer review report Type Example External, internal, target site Extract concentration, Frequency, single/repeated Individual Adult (male/female), pediatric, infant/neonate

Toxicological Risk

Matching data = reduced uncertainty

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Can be useful for determining whether a chemical/compound present or released from a medical device presents a systemic toxic, genotoxic, carcinogenic reproductive, or developmental toxicological risk (other biological endpoints on a case-by-case basis).

Why Conduct a Toxicological Risk Assessment?

“For devices where the patient-contacting portions may contain potentially toxic chemicals, the evaluation of safety should include both chemical risk (i.e., the level

f toxicological concern) and the type and duration of exposure.” – Section VII

Chemical Assessment, page 42 of CDRH (2016) Biocompatibility Guidance www.fda.gov

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When investigating presence/release of a chemical(s) of toxicological concern in a patient contacting material(s)

“In addition, chemical analyses can be used to assess the toxicological risk of the chemicals that elute from devices.” – Section B. Identification of Potential Risks, page 8, CDRH (2016) Biocompatibility Guidance Note: “However, chemical analysis is usually insufficient to identify all of the risks of the device in its final finished form, because it will not consider aspects of the finished device such as surface properties (e.g., rough versus polished surface) or device geometry that could affect the biological response in certain scenarios (e.g., thrombogenicity, implantation).”

www.fda.gov

When to consider toxicological risk assessment?

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www.fda.gov

When addressing a positive genotoxicity test result

“In the event of a positive result, we recommend further investigation to identify the source of the genotoxin. We recommend this information be used to help evaluate the overall benefit-risk of the device using a toxicological risk assessment with respect to carcinogenicity, as described in Section VI.G, below.” – Section F Genotoxicity, page 38, CDRH (2016) Biocompatibility Guidance

When to consider toxicological risk assessment?

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Devices made from novel materials (i.e., never before used in a legally US-

marketed medical device)

When to consider toxicological risk assessment?

www.fda.gov

Per CDRH (2016) Biocompatibility Guidance, Section VII Chemical Assessment page 43

New chemicals used to modify material formulations or device manufacturing

processes

Devices made from chemicals with known toxicities (e.g., carcinogenicity), where

new biocompatibility testing is rarely conducted

Devices made from materials intended to change (e.g., in situ polymerizing or

absorbable materials)

Unexpected biocompatibility test findings
“Long history of safe use” rationales

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Current Status of CDRH Recognition of ISO 10993-17:2002(R)2012 – “Establishment of allowable limits for leachable substances”

www.fda.gov

Clause Exclusions 1. Scope 2. Normative references 3. Terms and definitions 4. General principles for establishing allowable limits 5. Establishment of tolerable intake (TI) for specific leachable substances 6. Calculation of tolerable exposure (TE) Clause 6.2.1; Clause 6.3.2 b) 2) and Equation 6; Clause 6.3.3 and Equation 7 7. Feasibility evaluation Clause 7.1 b) Paragraph 2 Clause 7.2, Words, either and or economically 8. Benefit evaluation 9. Allowable limits

10. Reporting requirements

Annexes Annex C, Clause C.2.1

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“If data are not available to evaluate the safety of a compound, then

the concept of Threshold of Toxicological Concern (TTC)16 can be used to assess some biocompatibility endpoints.” – Section C.

Considering Available Information to Identify and Mitigate Risks 1 Literature and

ther publicly available information, page 9, CDRH (2016) Biocompatibility

Guidance

Threshold of Toxicological Concern (TTC)

www.fda.gov

“The TTC approach can be used to determine if quantification

without chemical identification is sufficient to assess the toxicity risk of the device.53 Otherwise, chemical identification is needed. ”

– Section G. Carcinogenicity, page 40, CDRH (2016) Biocompatibility Guidance

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Margin of Safety (MOS)

Dose Toxicological Threshold Dose ÷

Threshold of Toxicological Concern (TTC)

(ICH M7)

Tolerable Intake (TI)/Point of Departure (POD)
Amount present
Total extractable amount
Exposure estimate

www.fda.gov

0.1 1 10

MOS Value

Two Non-Targeted Analytes (Example)

Generally Favorable Toxicological Concern?

Because MOS can be based on different types of toxicological and dose-based data, expert interpretation is used to derive and interpret MOS values

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Textbook toxicological risk assessment method assumes identity
f the chemical/compound of interest is known

How important is identification in toxicological risk assessment of medical device extractables?

www.fda.gov

Background

When screening for non-targeted extractables, identification of

extractables can be challenging for the analytical chemist

Especially for extractables unexpected to be present
When spectra data of an unexpected analyte does not have

a clear library match or no match at all

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Analytical approaches for identifying a non-targeted extractable

adequate for toxicological risk assessment is of interest in recent literature

How important is identification in toxicological risk assessment of medical device extractables?

www.fda.gov

Background

For medical device extractables, toxicological risk assessments

is applied to extractables where molecular structure is elucidated to a confident/confirmed level, less-than-confident level, or not elucidated at all

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Selection Criteria

Submissions (n=6) received 2019, prolonged/long-term device contact, adult, non-targeted analysis, maximum exposure dose estimate

Scope Evaluate occurrence of reported MOS values based on identity (i.e., chemical molecular structure) and type of toxicological threshold

How important is identification in toxicological risk assessment of medical device extractables?

www.fda.gov

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Molecular Structure Total MOS Values N/A 529 Names/CAS #’s Complete 191 Other Incomplete 125 Unidentified Absent 11

How important is identification in toxicological risk assessment of medical device extractables?

Summary of Reported MOS values

www.fda.gov

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20 40 60 80 100 120 140 160 180

<0.001 ≤0.001-<0.01 ≤0.01-<0.1 ≤0.1-<1 ≤1-<10 ≤10-<100 ≤100-<1000 >=1000

Number of MOS Values

Name/CAS # TI (POD) Name/CAS # TTC (ICH M7) Name/CAS # TTC (Cramer Class) Other TI (POD) Other TTC (ICH M7) Other TTC (Cramer Class) Unidentified TI (POD) Unidentified TTC (ICH M7) Unidentified TTC (Cramer Class) Implant/Externally Communicating Prolonged/Long-Term Contact Adults non-Targeted Analysis Reports = 6

Grouping Reported MOS Values by Identity

Note: Data does not imply risk assessment outcome Toxicity data rich Toxicity data poor

(Suspected mutagenic carcinogen)

Toxicity data poor

(Suspected systemic toxicant) Name/CAS (TI/POD) (tox data rich) Unidentified (TTC ICH M7) (identity & tox data poor)

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>1 MOS values: almost always occur when complete molecular structure and TI/POD are reported

Grouping Reported MOS Values by Identity

Medical device MOS values evaluated support identification is important when assessing whether a non-targeted extractable will not raise a toxicological concern without potential need for additional justification

<1 MOS values: almost always occur when absence of molecular structure and TTC are reported

Summary/Conclusion

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ISO Technical Specification (TS) 21726 “Biological evaluation of medical devices — Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents”

ISO TC 194 10993 Standards

www.fda.gov

Published by ISO in February 2019
Currently under review by CDRH for status of recognition
Recognition will be published at FDA Recognized Consensus Standards database

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm

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ISO 10993-7:2008/DAM 1:2018(E) “Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals”

ISO TC 194 10993 Standards (cont.)

www.fda.gov

Comments resolved in ISO TC 194 WG11 meeting in Berlin
Draft amendment with resolved comments sent to Secretariat for balloting

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ISO TC 194 10993 Standards (cont.)

New Work Item Proposal (NWIP) to revise ISO 10993-7 “Biological evaluation of medical devices — Part 7: Ethylene

xide sterilization residuals”

www.fda.gov

Initiating NWIP
Working draft (WD) to begin in 2019
Initial discussion of WD at next ISO TC 194 WG11 meeting

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Revision of ISO Biological evaluation of medical devices— Part 17: “Toxicological risk assessment of medical device constituents”

ISO TC 194 10993 Standards (cont.)

www.fda.gov

ISO TC 194 WG11 Writing Team is creating working draft (WD)
WD to be balloted June/July 2019
WD to be discussed at next ISO TC 194 WG11 meeting (Q4 2019,

Arlington, VA)

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ISO TC 194 10993 Standards (cont.) ISO 10993-17 Current (2002(R)2012) vs Working Draft

ISO 10993-17:2002(R)2012 Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances 1. Scope 2. Normative references 3. Terms and definitions 4. General principles for establishing allowable limits 5. Establishment of tolerable intake (TI) for specific leachable substances 6. Calculation of tolerable exposure (TE) 7. Feasibility evaluation 8. Benefit evaluation 9. Allowable limits 10. Reporting requirements

Current Working Draft (WD)

www.fda.gov

ISO WD 10993-17 (current) Biological evaluation of medical devices - Part 17: Toxicological risk assessment of medical device constituents 1. Scope 2. Normative references 3. Terms and definitions 4. Overview of toxicological risk assessment within the biological evaluation process 5. Planning and scoping 6. Hazard identification 7. Dose-response assessment 8. Exposure assessment 9. Risk characterization 10. Risk control 11. Reporting requirements

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Contacting CDRH

a) Pre-submission

https://www.fda.gov/media/114034/download

b) Technical Contacts on Guidance Documents c) Recognized Consensus Standards

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm

www.fda.gov

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Acknowledgements

CDRH Office of Science and Engineering Laboratories (OSEL): technical

colleagues and managers

CDRH Office of Product Evaluation and Quality (OPEQ)*: regulatory colleagues

and managers

Colleagues from industry for valuable conversations
Society of Toxicology, Medical Device and Combination Products Specialty

Section for hosting this event

www.fda.gov

* 5/1/2019 reorganization combined Office of Device Evaluation (ODE), Office of Compliance (OC) & Office of Surveillance and Biometrics (OSB)

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Thank you! Questions?

www.fda.gov

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Supplemental Information

ISO 10993-17:2002(R)2012 Clauses Excluded from CDRH Recognition

(Recognition Number 2-237, July 26, 2016)

Annex C (informative) Conversion of allowable limits for systemic exposure and for body surface contact to maximum dose to patient from a medical device

www.fda.gov